Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Jennifer J. Griggs, Pamela B. Mangu, Holly Anderson, Edward P. Balaban, James J. Dignam, William M. Hryniuk, Vicki A. Morrison, T. May Pini, Carolyn D. Runowicz, Gary L. Rosner, Michelle Shayne, Alex Sparreboom, Lara E. Sucheston, and Gary H. Lyman Jennifer J. Griggs, University of Michigan, Ann Arbor, MI; Pamela B. Mangu, American Society of Clinical Oncology, Alexandria, VA; Holly Anderson, Breast Cancer Coalition of Rochester; Michelle Shayne, University of Rochester Medical Center, Rochester; Lara E. Sucheston, Roswell Park Cancer Institute, Cancer Prevention and Control, Buffalo, NY; Edward P. Balaban, University of Pittsburgh Cancer Centers Network, Pittsburgh, PA; James J. Dignam, University of Chicago, Chicago, IL; William M. Hryniuk, CarePath, Toronto, Ontario, Canada; Vicki A. Morrison, University of Minnesota Veterans Affairs Medical Center, Minneapolis, MN; T. May Pini, Medical Oncology, Houston, TX; Carolyn D. Runowicz, Florida International University, Miami, FL; Gary L. Rosner, Johns Hopkins University, Baltimore, MD; Alex Sparreboom, St Jude Children’s Research Hospital, Memphis, TN; and Gary H. Lyman, Duke University and the Duke Cancer Institute, Durham, NC. American Society of Clinical Oncology Clinical Practice Guideline Committee Approved: November 9, 2011. Editor’s note: This is the complete American Society of Clinical Oncology (ASCO) Clinical Practice Guideline on Appropriate Chemotherapy for Obese Adult Patients with Cancer, and it provides the recommendations with comprehensive discussions of the relevant literature for each. The Executive Summary of the guideline and Data Supplements with evidence tables and other tables and figures are available at www.asco.org/guidelines/wbd. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article. Corresponding author: American Society of Clinical Oncology, 2318 Mill Rd, Suite 800, Alexandria, VA 22314; e-mail: [email protected]. © 2012 by American Society of Clinical Oncology A B S T R A C T Purpose To provide recommendations for appropriate cytotoxic chemotherapy dosing for obese adult patients with cancer. Methods The American Society of Clinical Oncology convened a Panel of experts in medical and gynecologic oncology, clinical pharmacology, pharmacokinetics and pharmacogenetics, and biostatistics and a patient representative. MEDLINE searches identified studies published in English between 1996 and 2010, and a systematic review of the literature was conducted. A majority of studies involved breast, ovarian, colon, and lung cancers. This guideline does not address dosing for novel targeted agents. Results Practice pattern studies demonstrate that up to 40% of obese patients receive limited chemotherapy doses that are not based on actual body weight. Concerns about toxicity or overdosing in obese patients with cancer, based on the use of actual body weight, are unfounded. Recommendations The Panel recommends that full weight– based cytotoxic chemotherapy doses be used to treat obese patients with cancer, particularly when the goal of treatment is cure. There is no evidence that shortor long-term toxicity is increased among obese patients receiving full weight– based doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese who are administered full weight– based doses. Clinicians should respond to all treatment-related toxicities in obese patients in the same ways they do for non-obese patients. The use of fixed-dose chemotherapy is rarely justified, but the Panel does recommend fixed dosing for a few select agents. The Panel recommends further research into the role of pharmacokinetics and pharmacogenetics to guide appropriate dosing of obese patients with cancer. INTRODUCTION Optimal doses of chemotherapy drugs or drug combinations are generally established through randomized controlled clinical trials (RCTs). In adult patients with cancer, drug dosing has traditionally been based on a patient’s estimated body surface area (BSA).1 Despite continuing controversy concerning the value of dose escalation and intensification schedules, there exists compelling preclinical and clinical evidence that reductions from standard dose and dose-intensity may compromise disease-free (DFS) and overall survival (OS) in the curative setting.2-7 Furthermore, a number of authors have suggested that the optimal delivery of cancer chemotherapy should be considered an indicator of quality of care.3,8,9 Despite studies confirming the safety and importance of full weight– based chemotherapy dosing (Data Supplement 1 at www.asco.org/guidelines/ wbd), many overweight and obese patients continue to receive limited chemotherapy doses.10-13 Many oncologists continue to use either ideal body weight or adjusted ideal body weight or to cap the BSA at, for example, 2.0 m2 rather than use actual body weight to calculate BSA. Practice pattern studies demonstrate that up to 40% of obese patients receive limited doses that are not based on actual body weight.10,12-17 Moreover, considerable variation in the dosing of chemotherapy in overweight and obese individuals with cancer has been documented,3,13,14,16,18-22 suggesting considerable uncertainty among physicians about optimal dose selection. Such uncertainty likely arises from the fact that many published © 2012 by American Society of Clinical Oncology 1 Griggs et al clinical trials present neither the planned chemotherapy dosing nor the delivered dose-intensity.23 Because there are no available data, this guideline does not address adjusting chemotherapy doses because of ascites or anasarca for overweight or obese patients. Although nearly all cooperative groups specify that actual body weight be used in the calculation of BSA, the published reports from these trials rarely include the delivered dose-intensity specifically for obese patients.11 The practice of limiting cytotoxic (intravenous [IV] and oral) chemotherapy doses in overweight and obese patients may negatively influence the quality of care and outcomes at a population level, given the rise in rates of obesity both in the United States24,25 and globally.26 Rates of obesity have increased in recent years, reaching epidemic THE BOTTOM LINE ASCO GUIDELINE ASCO Guideline on Appropriate Chemotherapy Dosing for Obese Adult Patients With Cancer Intervention ● Recommendations for appropriate chemotherapy dosing for obese adult patients with cancer Target Audience ● Medical oncologists, pharmacists, oncology nurses Key Recommendations ● Panel recommends that full weight– based chemotherapy doses be used in the treatment of the obese patient with cancer, particularly when the goal of treatment is cure. ● Clinicians should respond to all treatment-related toxicities in obese patients with cancer in the same ways they do for non-obese patients. ● If a dose reduction is employed in response to toxicity, consideration should be given to the resumption of full weight– based doses for subsequent cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic function) has been resolved; there is no evidence to support the need for greater dose reductions for obese patients compared with non-obese patients. ● The use of fixed-dose cytotoxic chemotherapy is rarely justified (except for a few select agents). Methods ● Systematic review of the medical literature and analysis of the medical literature by the Update Committee of an Expert Panel Additional Information Data Supplements, including evidence tables, and clinical tools and resources can be found at www.asco.org/guidelines/wbd. 2 © 2012 by American Society of Clinical Oncology proportions in the United States. The Centers for Disease Control and Prevention estimates that a majority (⬎ 60%) of adult Americans have a body mass index (BMI) ⬎ 25 (overweight, obese, morbidly obese) and that this proportion is steadily increasing.24,25 Thus, appropriate chemotherapy dosing for obese patients with cancer is a significant issue for many oncology practices. Many cancers are more common in obese people, and cancer-specific outcomes tend to be worse among the obese.27 Poorer outcomes among obese patients are most likely multifactorial. Systemic chemotherapy at less than full weight– based dosing and unnecessary dose reductions may explain, in part, the significantly higher cancer mortality rates observed in overweight and obese individuals. Underdosing of chemotherapy is of particular concern in patients with chemoresponsive and potentially curable malignancies, for whom reductions in standard chemotherapy dose-intensity may increase the risk of disease recurrence and mortality. Concerns about overdosing in the obese patient with cancer based on the use of actual body weight are unfounded.10,13,19,28-30 Even when chemotherapy doses are calculated according to actual body weight, obese patients are less likely to have bone marrow suppression, supporting the safety of full weight– based dosing. Unlike body size, it is well established that comorbid conditions such as hepatic and renal dysfunction are relevant predictors of toxicity.31 There are few RCTs directly addressing optimal methods of dose calculation and delivery.2,32-36 A compelling body of evidence exists, however, supporting the important relationship between selection of chemotherapy doses (IV and oral) in adult patients with cancer and treatment efficacy and toxicity as well as pharmacokinetic correlates of dose selection.2,5,6,28,32,37-96 Ironically, in lean patients, in whom outcomes are less sensitive to full weight– based dosing,28,51 physicians are more likely to administer doses based on actual body weight, whereas obese patients, in whom outcomes are worse with a dose reduction of even 5%, are the most likely to have their doses reduced. Recent pharmacokinetic studies have clearly demonstrated that actual rather than ideal body weight should be used in dose calculations.97 GUIDELINE QUESTIONS The overarching question for this clinical practice guideline is: How should cytotoxic chemotherapy doses be selected for people with cancer who are obese? Specific questions addressed by the Panel include: 1. Is there evidence that full weight– based dosing increases toxicity in obese patients with cancer? 2. Is there evidence that less than full weight– based dosing compromises efficacy in obese patients with cancer? 3. If obese patients experience high-grade toxicity, should chemotherapy doses or schedules be modified differently from modifications used for non-obese patients with cancer? 4. Is a fixed dose (dose prescribed independently of weight or BSA) of cytotoxic chemotherapy ever justified? Are there unique dosing considerations for certain chemotherapeutic agents? 5. How should BSA be calculated? Specifically, what is the best formula for use in the obese patient with cancer? 6. What is the role of pharmacokinetic and/or phamacogenetic factors when determining optimal chemotherapy dose and delivery (bolus, infusional, therapeutic drug monitoring) for obese patients with cancer? ASCO Guideline on Weight-Based Dosing CLINICAL PRACTICE GUIDELINES Practice guidelines are systematically developed statements that assist practitioners and patients in making decisions about care. Attributes of good guidelines include validity, reliability, reproducibility, clinical applicability, flexibility, clarity, multidisciplinary process, review of evidence, and documentation. Guidelines may be useful in producing better care and decreasing cost. Specifically, use of clinical guidelines may provide: 1. Improvements in outcomes 2. Improvements in medical practice 3. A means for minimizing inappropriate practice variation 4. Decision support tools for practitioners 5. Points of reference for medical orientation and education 6. Criteria for self-evaluation 7. Indicators and criteria for external quality review 8. Assistance with reimbursement and coverage decisions 9. Criteria for use in credentialing decisions 10. Identification of areas in which future research is needed METHODS Panel Composition The American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines Committee convened an Expert Panel consisting of experts in clinical medicine and research relevant to appropriate chemotherapy dosing for obese adults with cancer, including medical and gynecologic oncologists, clinical pharmacologists, pharmacokinetic and pharmacogenetic experts, health services researchers, and biostatisticians. Academic and community practitioners and a patient representative were also part of the Panel. The Panel members are listed in Appendix Table A1. Literature Review and Analysis Literature search strategy. The MEDLINE and the Cochrane Collaboration Library electronic databases were initially searched with the date parameters of 1966 through October 2009, and articles published after the initial literature search were monitored through PubMed updates until October 2010 and added to the systematic review literature. The National Cancer Institute Physician Data Query database of clinical trials and the National Library of Medicine ClinicalTrials.gov database were also searched for ongoing trials. Electronic search results were supplemented with hand searching of selected reviews, expert consensus meeting notes, and reference lists from excluded articles. The literature search was limited to articles in English with human participants. MeSH headings and keywords searched were neoplasm, drug therapy, chemotherapy, dose, schedule, dose-intensity, obese, and overweight. The search excluded pediatric patients and patients with hematologic malignances undergoing bone marrow transplantation. Design or publication type included studies comparing different dosing approaches, and articles had to report one or more major toxicities or response criteria. MEDLINE search terms are included in Data Supplement 3 at www.asco.org/guidelines/wbd. A summary of the literature search results is provided in Data Supplement 4 at www.asco.org/guidelines/wbd. Inclusion and exclusion criteria. Articles were selected for inclusion in the systematic review if they were published English language studies on cytotoxic IV or oral chemotherapy dosing approaches for overweight or obese patients with cancer, excluding leukemias. Data were extracted from prospective or retrospective cohort studies that addressed withholding, delaying, early cessation, or reduction of chemotherapy doses, including capping doses (eg, at a BSA of 2.0 m2). Data were also extracted about treatment toxicity, DFS and OS, and quality-of-life outcomes. Systematic reviews of RCTs, meta-analyses, and other clinical practice guidelines were also conducted. Because of the paucity of data, this guideline does not address dosing for novel targeted agents such as tyrosine kinase inhibitors, immunotherapies (eg, interleukin-2, interferon), or monoclonal antibodies. Pharmacokinetic studies with pharmacodynamic or clinical outcomes with appropriate controls were also included. Meeting abstracts, letters, commentaries, editorials, case reports, nonsystematic (narrative) reviews, and studies limited to pediatric patients were excluded. Studies also were excluded if they addressed dose selection of noncytotoxic agents, such as tamoxifen or finasteride. Data extraction. Primary outcome measures of interest included OS, disease-specific survival, DFS, relapse-free survival, event-free survival, progression-free survival (PFS), and treatment-related toxicities. Secondary outcomes and/or other data elements of interest included quality of life and costs of care. Abstracts were reviewed, and articles were deemed appropriate for full text review and data extraction by one reviewer and reviewed by the Co-Chairs as well. Screening and data extraction were completed using DistillerSR (Evidence Partners, Ottawa, Ontario, Canada) and data were exported into evidence tables (evidence tables provided in Data Supplements 1 and 2 at www.asco.org/guidelines/wbd). Data were extracted by one reviewer and subsequently checked for accuracy by a second reviewer. Disagreements were resolved by discussion and by consultation with Panel Co-Chairs, if necessary. Study Quality and Limitations of the Literature There are no prospective randomized studies comparing full weight– based chemotherapy dose selection and non–full weight– based dose selection. Retrospective analyses of randomized trials and comparative observational studies comprise the majority of the studies included in this guideline. This guideline is based on evidence derived primarily from subgroup analyses and registry data. Although the results are important, it should be clear to the reader that the evidence base for this guideline is necessarily different from those for other ASCO guidelines (eg, Antiemetics or Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer, which rely on large, prospective randomized trials). Consensus Development Based on Evidence The entire Panel met once in person, and additional work on the guideline was completed through teleconferences and electronic communications. The purpose of the Panel meeting was to refine the clinical questions, draft guideline recommendations, and distribute writing assignments. All members of the Panel participated in the preparation of the draft guideline document, which was then disseminated for review by the entire Panel. The guideline was submitted to Journal of Clinical Oncology (JCO) for peer review. Feedback from external reviewers was also solicited. The content of the guideline and the manuscript were reviewed and approved by the ASCO Clinical Practice Guideline Committee before publication. Definition of Terms A glossary of terms, including information on calculating BSA (eg, Mosteller, Dubois and Dubois, Haycock, Gehan and George, Boyd formulas) and toxicity grades, appears in Data Supplement 5 at www.asco.org/ guidelines/wbd. Guideline Policy This clinical practice guideline is not intended to substitute for the independent professional judgment of the treating physician. Practice guidelines do not account for individual variation among patients and may not reflect the most recent evidence. This guideline does not recommend any particular product or course of medical treatment. Use of the practice guideline is voluntary. Guideline and Conflicts of Interest The Expert Panel was assembled in accordance with the ASCO Conflict of Interest Management Procedures for Clinical Practice Guidelines (summarized at http://www.asco.org/guidelinescoi). Members of the Panel completed the ASCO disclosure form, which requires disclosure of financial and other interests that are relevant to the subject matter of the guideline, including relationships with commercial entities that are reasonably likely to experience direct regulatory or commercial impact as the result of promulgation of the © 2012 by American Society of Clinical Oncology 3 Griggs et al guideline. Categories for disclosure include employment relationships, consulting arrangements, stock ownership, honoraria, research funding, and expert testimony. In accordance with the Procedures, the majority of the members of the Panel did not disclose any of these relationships. Revision Dates At annual intervals, the Panel Co-Chairs and two Panel members, designated by the Co-Chairs, will determine the need for revisions to the guideline based on an examination of current literature. If necessary, the entire Panel or an Update Committee will reconvene to discuss potential changes. When appropriate, the Panel will recommend a revised guideline to the ASCO Clinical Practice Guideline Committee for review and approval. Other Guidelines and Consensus Statements There are no published guidelines that address appropriate chemotherapy dosing for obese patients with cancer. GUIDELINE RECOMMENDATIONS The overarching question for this clinical practice guideline is: Should actual body weight be used to select chemotherapy doses in obese individuals with cancer? Overweight and obesity are both labels for ranges of weight that are greater than what is generally considered healthy for a given height. The terms also identify ranges of weight that have been shown to increase the likelihood of certain diseases and other health problems. For adults, overweight and obesity ranges are determined by using weight and height to calculate BMI. Although for most individuals BMI correlates with amount of body fat, BMI is not a direct measure of body fat. As a result, some people, such as athletes, may have a BMI that identifies them as overweight even though they do not have excess body fat. For more information about BMI, visit the Centers for Disease Control and Prevention Web site.98 An adult who has a BMI between 18.5 and 24.9 kg/m2 is considered normal weight; an adult who has a BMI between 25 and 29.9 kg/m2 is considered overweight; an adult who has a BMI of ⱖ 30 kg/m2 is considered obese; an adult who has a BMI ⬎ 40 kg/m2 is considered morbidly obese (or ⬎ 35 kg/m2 with comorbid conditions). More information about interpreting BMI for adults is provided in Data Supplement 6 at www.asco.org/guidelines/wbd. Table 1 provides a summary of the following guideline recommendations. Clinical Question 1 Is there evidence that full weight– based dosing increases toxicity in obese patients with cancer? Recommendation 1.1. The Panel recommends that actual body weight be used when selecting cytotoxic chemotherapy doses regardless of obesity status. There is no evidence that short- or long-term toxicity is increased among obese patients receiving full weight– based chemotherapy doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese when administered full weight– based doses. Literature review and analysis. Observational studies and retrospective analyses of participants in clinical trials have not demonstrated increased hematologic or nonhematologic toxicity in obese patients receiving chemotherapy doses calculated using actual body weight. For example, no excess toxicity was observed among patients with small-cell lung cancer when actual weight was used to calculate chemotherapy doses.29 In a retrospective analysis of CALGB (Cancer and Leukemia Group B) Protocol 8541, obese patients receiving full 4 © 2012 by American Society of Clinical Oncology weight– based dosing of adjuvant cyclophosphamide, doxorubicin, and fluorouracil had no excess grade 3 hematologic or nonhematologic toxicity at any of the three dose levels in the study compared with non-obese patients.28 In obese patients receiving full weight– based doses of cyclophosphamide, methotrexate, and fluorouracil in the adjuvant treatment of breast cancer, patients with the highest BMIs had the highest leukocyte nadir values, or leukocyte nadirs were less pronounced among obese patients compared with non-obese patients.30 A large study of 9,672 patients with breast cancer treated in practices across the United States with adjuvant doxorubicin and cyclophosphamide demonstrated that the likelihood of febrile neutropenia, if anything, decreased as BMI increased among those patients who received full weight– based dosing.13 Similar findings were reported in the treatment of 59 women with endometrial or ovarian cancer and BSA ⬎ 2.0 m2 who received paclitaxel and carboplatin based on actual body weight.99 On the basis of these studies and others included in the systematic review,100-103 the Panel concluded that there is no evidence indicating higher rates of hematologic or nonhematologic toxicity among obese patients who received full weight– based doses. The heavier a patient is, even fully dosed, the less likely he or she is to have febrile neutropenia, especially in the absence of additional comorbid illness. Recommendation 1.2. The Panel recommends full weight–based chemotherapy dosing for morbidly obese patients with cancer, subject to appropriate consideration of other comorbid conditions. Data are extremely limited regarding optimal dose selection among the morbidly obese and other special subgroups. More studies are needed to evaluate optimal agents and agent combinations for obese and morbidly obese patients with cancer; however, on the basis of available information, it appears likely that the same principles regarding dose selection for obese patients apply to the morbidly obese. Literature review and analysis. A search of MEDLINE and the Cochrane Collaboration Library was conducted to identify literature specifically addressing treatment of patients who are morbidly obese. Nine articles104-112 were found, a majority of which were small observational studies or case reports and primarily presented data on the pharmacokinetics of chemotherapy in this subgroup. For this reason, there are no separate recommendations for morbidly obese patients in this guideline. From the available evidence, it seems that morbidly obese patients being treated with curative intent and receiving full weight– based doses were no more likely to experience toxicity than lean patients.113 Clinicians need to calculate full weight– based dosing and use clinical judgment when monitoring toxicity, as they would for all patients.114 In this same early study, it was recommended that BSA be recalculated when body weight has changed by more than 5% to 10%.114 However, there are limited data on recalculating dose when body weight changes, and more research studies are needed. The Panel recognizes that there may be cases in which obese patients have other serious medical problems, and it encourages clinicians to use judgment when dosing, as they would if the patients were not obese (eg, heart, renal, pulmonary problems). Clinical Question 2 Is there evidence that less than full weight– based dosing compromises efficacy in obese patients with cancer? Recommendation 2.1. The Panel recommends that full weight– based chemotherapy doses (IV and oral) be used in the treatment of the obese patient with cancer, particularly when the goal of treatment ASCO Guideline on Weight-Based Dosing Table 1. Clinical Questions and Recommendations Clinical Question Recommendation 1. Is there evidence that full weight–based Recommendation 1.1: The Panel recommends that actual body weight be used when selecting cytotoxic chemodosing increases toxicity in obese patients therapy doses regardless of obesity status. There is no evidence that short- or long-term toxicity is increased with cancer? among obese patients receiving full weight–based chemotherapy doses. Most data indicate that myelosuppression is the same or less pronounced among the obese than the non-obese administered full weight–based doses. Recommendation 1.2: The Panel recommends full weight–based chemotherapy dosing for morbidly obese patients with cancer, subject to appropriate consideration of other comorbid conditions. Data are extremely limited regarding optimal dose selection among the morbidly obese and other special subgroups. More studies are needed to evaluate optimal agents and agent combinations for obese and morbidly obese patients with cancer; however, based on available information, it seems likely that the same principles regarding dose selection for obese patients apply to the morbidly obese. 2. Is there evidence that less than full Recommendation 2.1: The Panel recommends that full weight–based chemotherapy doses (IV and oral) be used weight–based dosing compromises in the treatment of the obese patient with cancer, particularly when the goal of treatment is cure. Selecting efficacy in obese patients with cancer? reduced doses in this setting may result in poorer disease-free and overall survival rates. There are compelling data in patients with breast cancer that reduced dose-intensity chemotherapy is associated with increased disease recurrence and mortality. Although data in other malignancies are more limited, based on improved survival observed with chemotherapy compared with controls, a dose-response relationship exists for many responsive malignancies. Therefore, although data are not available to address this question for all cancer types, in the absence of data demonstrating sustained efficacy for reduced dose chemotherapy, the Panel believes that the prudent approach is to provide full weight–based chemotherapy dosing to obese patients with cancer, especially those receiving treatment with curative intent. Most of the data in support of full weight–based dosing come from the treatment of early-stage disease. Data supporting the use of full weight–based doses in the advanced disease setting are limited. 3. If an obese patient experiences highRecommendation 3.1: Clinicians should follow the same guidelines for dose reduction, regardless of obesity grade toxicity, should chemotherapy status, for all patients, depending on the type and severity of toxicity, any comorbid conditions, and whether doses or schedules be modified the treatment intention is cure or palliation. There is no evidence to support the need for greater dose differently from modifications used for reductions for obese patients compared with non-obese patients. If a dose reduction is employed in response non-obese patients with cancer? to toxicity, consideration should be given to the resumption of full weight–based doses for subsequent cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic function) has been resolved. The Panel recognizes the need for clinicians to exercise judgment when providing care for patients who have experienced grade 3 or 4 chemotherapy toxicity. The presence of obesity alone should not alter such clinical judgment. 4. Is the use of fixed-dose (dose prescribed Recommendation 4.1: The Panel recommends consideration of fixed dosing only with select cytotoxic agents independently of weight or BSA) cytotoxic (eg, carboplatin and bleomycin). On the basis primarily of neurotoxicity concerns, vincristine is capped at a chemotherapy ever justified? Are there maximum dose of 2.0 mg when used as part of the CHOP and CVP regimens. Several other cytotoxic chemounique dosing considerations for certain therapeutic agents have been used in clinical trials at a fixed dose independent of patient weight or BSA. chemotherapeutic agents? However, it is not clear that fixed dosing is optimal for any of these other agents. 5. How should BSA be calculated? Recommendation 5.1: The Panel recommends that BSA be calculated using any of the standard formulae. There Specifically, what is the best formula for is no evidence to support one formula for calculating BSA over another. use with the obese patient with cancer? 6. What is the role of pharmacokinetic and/ Recommendation 6.1: The Panel recommends further research into the role of pharmacokinetic and or phamacogenetic factors when pharmacogenetic information for guiding the dosing of IV and oral chemotherapeutic agents for adult patients determining optimal chemotherapy dose with cancer who are obese. It should be emphasized that there is a paucity of information on the influence of and delivery (bolus, infusional, therapeutic obesity on the pharmacokinetics of most anticancer drugs from properly powered trials. This is the result, in drug monitoring) for obese patients with part, of empiric eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses cancer? performed and published for this subpopulation. Overall, there are insufficient pharmacokinetic data to reject the recommendation to use a full weight–based dosing strategy for chemotherapeutic agents in patients with cancer who are obese, regardless of route of administration and/or infusion time. Abbreviations: BSA, body surface area; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP, cyclophosphamide, vincristine, prednisone; IV, intravenous. is cure. Selecting reduced doses in this setting may result in poorer DFS and OS rates. There are compelling data in patients with breast cancer that reduced dose-intensity chemotherapy is associated with increased disease recurrence and mortality. Although data in other malignancies are more limited, based on improved survival observed with chemotherapy compared with controls, a dose-response relationship exists for many responsive malignancies. Therefore, although data are not available to address this question for all cancer types, in the absence of data demonstrating sustained efficacy for reduced-dose chemotherapy, the Panel believes that the prudent approach is to provide full weight– based chemotherapy dosing to obese cancer patients, especially those receiving treatment with curative intent. Most of the data in support of full weight– based dosing come from the treatment of early-stage disease. Data supporting the use of full weight– based doses in the advanced disease setting are limited. Literature review and analysis. Retrospective analyses and observational studies suggest that dose limits in obese patients may com- promise DFS and OS rates.115-118 An analysis of outcomes among obese patients treated in CALGB 8541 demonstrated that obese patients who received ⬍ 95% of the expected chemotherapy (based on full weight– based dosing) had worse failure-free survival rates.28 Additional data supporting the use of full weight– based dosing came from a retrospective analysis of four adjuvant chemotherapy studies conducted by the International Breast Cancer Study Group (previously the Ludwig Study Group). In this analysis, obese patients with estrogen receptor–negative breast cancer who received ⬍ 85% of the dose experienced a higher relapse rate and had a lower survival rate.51 Clinical Question 3 If an obese patient experiences high-grade toxicity, should chemotherapy doses or schedules be modified differently from modifications used for non-obese patients with cancer? Recommendation 3.1. Clinicians should follow the same guidelines for dose reduction, regardless of obesity status, for all patients, © 2012 by American Society of Clinical Oncology 5 Griggs et al depending on the type and severity of toxicity, any comorbid conditions, and whether the treatment intention is cure or palliation. There is no evidence to support the need for greater dose reductions for obese patients compared with non-obese patients. If a dose reduction is employed in response to toxicity, consideration should be given to the resumption of full weight– based doses for subsequent cycles, especially if a possible cause of toxicity (eg, impaired renal, hepatic function) has been resolved. The Panel recognizes the need for clinicians to exercise judgment when providing care for patients who have experienced grade 3 or 4 chemotherapy toxicity. The presence of obesity alone should not alter such clinical judgment. Literature review and analysis. There are no RCTs that specify differential management of moderate to severe toxicity (grades 3 to 4) according to obesity status (Glossary in Data Supplement 5 at www.asco .org/guidelines/wbd provides more information on toxicity grades). Similarly, no observational studies describe BMI-based management of toxicities from chemotherapy. Given the lack of evidence citing harms in differential treatment, the Panel recommends clinicians respond to treatment-related toxicities in obese patients with cancer in the same ways they do for non-obese patients with cancer. Excess toxicity usually results from the fact that the patient has reduced drug elimination in reference to the dose of one (or more) chemotherapeutic agents. A return to initial dosing after toxicity is resolved rarely occurs unless the reason for the toxicity is clearly established and fully resolved. Thus, the dose should only be increased to the initial dose if it is established that drug elimination has improved (eg, improvement in renal function, return of bilirubin to normal, significant improvement in performance status). Obesity status alone should not play a role in dose modifications in response to toxicity. Clinical Question 4 Is a fixed dose (dose prescribed independently of weight or BSA) of cytotoxic chemotherapy ever justified? Are there unique dosing considerations for certain chemotherapeutic agents? Recommendation 4.1. The Panel recommends consideration of fixed dosing only with select cytotoxic agents (eg, carboplatin and bleomycin). On the basis primarily of neurotoxicity concerns, vincristine is capped at a maximum dose of 2.0 mg when used as part of the CHOP (cyclophosphamide, hydroxydoxorubicin [doxorubicin], vincristine, prednisone) and CVP (cyclophosphamide, vincristine, prednisone) regimens. Several other cytotoxic chemotherapeutic agents have been used in clinical trials at a fixed dose independent of patient weight or BSA. However, it is not clear that fixed dosing is optimal for any of these other agents. Literature review and analysis. The Panel recommends consideration of fixed dosing only with a select group of agents. For example, carboplatin clearance depends on glomerular filtration rate (GFR), and doses are calculated best using the Calvert formula119,120 (total dose [mg] ⫽ [AUC (target area under the plasma concentration-time curve)] ⫻ [GFR ⫹ 25]) to achieve a targeted AUC. The GFR used in the Calvert formula to calculate the AUC dosing should not exceed 125 mL/min. The maximum carboplatin dose should not exceed AUC (mg ⫻ min/mL) ⫻ 150 mL/min. Because carboplatin clearance is dictated by renal filtration, and GFR correlates with BSA, dosing of carboplatin in the obese patient with cancer based on GFR may be most reasonable. Note that the US Department of Health and Human Services issued the “Follow-Up for Information Letter Regarding AUC-Based Dosing of Carboplatin” on October 22, 2010,121 about the 6 © 2012 by American Society of Clinical Oncology AUC-based dosing of carboplatin. The National Institute for Standards and Technology standardized the measurement of serum creatinine using isotope dilution mass spectrometry (IDMS), and reagents for older methodologies should no longer be available. All laboratories in the United States by 2010 should have switched to the IDMS measurement. Older and other122,123 methods were not standardized, and this led to variable creatinine values; the use of a single correction factor to convert IDMS creatinine values to non-IDMS creatinine values will not work across all laboratories. If the total carboplatin dose is calculated based on an estimated GFR using an IDMS-measured serum creatinine and the Calvert formula, carboplatin dosing could be higher than desired and could result in increased toxicity. There are several agents that are sometimes prescribed at a fixed dose or capped based on the dose that was used in clinical trials. The usual adult dose of bleomycin for testicular cancer is a fixed dose in a BEP (bleomycin, etoposide, cisplatin) regimen.124 In the R-CHOP (rituximab plus CHOP), CHOP, and CVP regimens, the dose of vincristine is capped at a maximum of 2 mg.125,126 Of note, the use of flat-fixed dosing of irinotecan has been previously examined but not in large clinical trials. In one trial, just 26 patients were treated with a fixed irinotecan dose of 600 mg over a 90-minute infusion, and pharmacokinetic and pharmacodynamic parameters were compared with those of 47 patients treated with irinotecan at a dose of 350 mg/m2. No significant differences were observed, and hematologic adverse effects were also noted to be similar.45 In another study of 82 patients receiving irinotecan as a 90-minute IV infusion from 175 to 350 mg/m2, BSA was not a predictor of clearance or other drug pharmacokinetics.127 In general oncologic practice, dosing for irinotecan remains based on BSA. There are other agents that have been used in fixed doses in non-RCTs of the treatment of specific cancers in unique patient populations; these include agents such as metronomic cyclophosphamide128-133 and capecitabine.134 Fixed dosing based on BMI or BSA categories is possible and has been proposed for some agents (eg, cisplatin), but such approaches have never been prospectively evaluated.107 Clinical Question 5 How should BSA be calculated? Specifically, what is the best formula for use in the obese patient with cancer? Recommendation 5.1. The Panel recommends that BSA be calculated using any of the standard formulas (eg, Mosteller, DuBois and Dubois, Haycock, Gehan and George, Boyd formulas). There is no evidence to support one formula for calculating BSA over another. Literature review and analysis. It should be noted that the formulas for calculating BSA were not developed for use in the obese or morbidly obese and/or those with multiple comorbid conditions and do not take into account patient sex. In fact, there may be noticeable differences (⬎ 10%) in calculated values of BSA, especially at the extremes of weight and/or height, resulting in noticeable differences in dosing. There are ongoing efforts to establish a new BSA equation suitable for a typical 21st century population, because ⬎ 60% of adult Americans have BMIs ⬎ 25 kg/m2, and this proportion is steadily increasing.24,25 Data Supplement 5 at www.asco.org/guidelines/wbd includes BSA formulas currently used. ASCO Guideline on Weight-Based Dosing Clinical Question 6 What is the role of pharmacokinetic and/or pharmacogenetic factors when determining optimal chemotherapy dose and delivery (bolus, infusional, therapeutic drug monitoring) for obese patients with cancer? Recommendation 6.1. The Panel recommends further research into the role of pharmacokinetic and pharmacogenetic information for guiding the dosing of IV and oral chemotherapeutic agents for adult patients with cancer who are obese. It should be emphasized that there is a paucity of information on the influence of obesity on the pharmacokinetics of most anticancer drugs from properly powered trials. This is the result, in part, of empiric eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses performed and published for this subpopulation. Overall, there are insufficient pharmacokinetic data to reject the recommendation to use a full weight– based dosing strategy for chemotherapeutic agents in patients with cancer who are obese, regardless of route of administration and/or infusion time. Key measures of pharmacokinetics. Clearance is the most important pharmacokinetic parameter to consider when devising a dosing regimen for anticancer agents, because it is inversely related to the AUC. This parameter has clinical relevance because it correlates with clinical outcomes, although there are only a few examples in which the association is reproducible.135 For the majority of anticancer drugs, the liver is the principal organ mediating clearance. The accumulation of fat in the liver of obese patients may alter hepatic blood flow, and this pathologic change might have an impact on clearance. There is limited evidence of an increase in cytochrome P450 (CYP) 2E1 activity with obesity.136 Because few anticancer drugs are substrates for CYP2E1, the clinical significance of this finding is probably minimal. It has also been reported that the phenotypic activity of certain other isoforms of the CYP system, such as CYP3A, might be elevated in the obese,109 but it is unclear to what extent the findings can be definitively linked with any particular enzyme. In regard to phase II conjugation pathways, the results of studies with various drugs have suggested that increases in glucuronidation and sulfation occurring in obese individuals are proportional to total body weight.137 The other primary organs involved in the clearance of drugs are the kidneys. The processes involved in drug elimination through the kidneys include glomerular filtration, tubular secretion, and tubular reabsorption. The effect of obesity on these functions is not entirely clear.137 Studies of creatinine clearance, used to estimate GFR, have found increased, decreased, or similar GFR measurements in obese versus non-obese individuals.137 The variable results probably reflect the imprecision of creatinine as an index of the GFR. The pharmacokinetics of some but not all drugs may be altered in obese patients, but there is no single valid method to relate drug clearance to degree of obesity, so changes in drug dosing are not currently recommended. Nevertheless, it was suggested that lean body weight may be the best descriptor in 35% of the studies in which it was considered (across the therapeutic areas).68 From a physiologic standpoint, this seems plausible, because the major drug-clearing organs are constituents of lean body weight. Three observations regarding drug clearance and obesity were recently described138: (1) obese individuals exhibit higher absolute drug clearance than do their non-obese counterparts; (2) clearance does not increase linearly with total body weight; and (3) clearance and lean body weight are linearly correlated. Although findings from several studies are in agreement with observations (1) and (2), less evidence exists to support observation (3). In the context of anticancer drugs, the contention138 that a semi-mechanistically derived lean body weight is an ideal size descriptor to ascertain the impact of body composition on the clearance of anticancer drugs has been challenged.139 Pharmacokinetic changes in obese patients with cancer. There is a general paucity of information from sufficiently powered clinical studies on the influence of obesity on the pharmacokinetics of most anticancer drugs. This is the result, in part, of empiric eligibility restrictions from the outset in clinical trials and a lack of pharmacokinetic analyses performed and published for this subpopulation. In particular, dosing recommendations in oncology are usually based on results from clinical trials that included patients who are considered to be the typical weight of those likely to receive the drug in clinical practice. In many studies, the obese patient may be underrepresented. Therefore, extrapolation of dosing recommendations based on pharmacokinetic principles to this group must be performed arbitrarily when the dose is required to be standardized to a particular patient characteristic such as BSA. In a retrospective analysis, absolute clearance of cisplatin, paclitaxel, and troxacitabine97 was significantly higher in patients who were obese (BMI ⱖ 30 kg/m2) compared with lean controls (BMI ⱕ 25 kg/m2), but this was not observed for carboplatin, docetaxel, irinotecan, or topotecan.38,47,97 The data on the renally cleared drugs cisplatin and troxacitabine are consistent with the notion that tubular secretion, rather than glomerular filtration, is disproportionately increased in obese individuals.140 It is possible that the impact of obesity on the clearance of the hepatically cleared drug paclitaxel originates from changes in activity of one or more CYP enzymes. Nonetheless, a similar effect of obesity on absolute clearance was not observed for the structurally related drug docetaxel. This discrepancy might be related to the finding that for docetaxel, the volume of distribution and the half-life of the terminal phase were statistically significantly increased in the obese. This has been described previously for other hydrophobic drugs that have a high affinity for adipose tissue.137 In addition, it is possible that paclitaxel and docetaxel are differentially influenced by hepatic transporters, because the function is altered in the obese. Regardless of the exact explanation for this incongruence, this example of the two taxanes clearly weakens the ability to support broad recommendations for dose calculation in the obese for drugs on the basis of physicochemical characteristics alone. Additional retrospective investigation has revealed that the absolute oral clearance of busulfan in obese and severely obese patients was significantly faster compared with that in normal-weight patients.141 When normalized to BSA, the oral clearance of busulfan was not significantly different between underweight, normal-weight, obese, or severely obese patients. Using the same classification scheme, there were also no significant differences in BSA-adjusted clearance among BMI classes in a study in which busulfan was administered intravenously.142 The potential usefulness of alternative weight descriptors in the equation for BSA to calculate drug dose in obese patients has been evaluated through a simulation analysis for various anticancer drugs.97 This work demonstrated that dose calculation in the obese on the basis of BSA using actual body weight is an appropriate strategy for cisplatin, paclitaxel, and troxacitabine. For carboplatin, consideration of either predicted normal weight or the mean of ideal and actual weight resulted in the best © 2012 by American Society of Clinical Oncology 7 Griggs et al prediction of systemic exposure in both men and women.97 In line with this finding, a prior analysis of data obtained in obese patients receiving carboplatin demonstrated that neither actual body weight nor ideal body weight was a perfect size descriptor and that the average of actual body weight and ideal body weight, obtained from a nonlinear mixed-effect modeling analysis, was the best predictor of carboplatin clearance within the formula integrating body weight and GFR.143 These findings for carboplatin, in conjunction with an assessment of cystatin C measurements as a marker of GFR, were confirmed in a large cohort of patients.122,144 For docetaxel and doxorubicin, applying lean body weight as a dosing scalar seems to have particular merit in predicting pharmacokinetic end points.137 Nonetheless, the weight of clinical and pharmacodynamic evidence suggests that full weight– based dosing of anthracyclines in patients with cancer who are obese is important in achieving optimal outcomes.13,28,97 Similarly, despite pharmacokinetic data suggesting that lean body weight predicts pharmacokinetic end points with docetaxel, Cooperative Group clinical trials have not limited doses of taxanes in obese patients with cancer.145 Taking currently available pharmacokinetic data into consideration, it seems that: (1) the pharmacokinetics of some, but not all, cancer drugs are significantly altered in the obese; (2) the selection of alternative size descriptors for dose calculation in the obese is drug specific and sex dependent and seems unrelated to intrinsic physicochemical properties or route of elimination; (3) obesity may affect, possibly in a drug-specific manner, treatment outcome through currently unknown mechanisms that are unrelated to pharmacokinetics; and (4) empiric decreases in drug dose for obese patients (eg, dose capping) are not supported by pharmacokinetic findings for any agent. Overall, there are insufficient pharmacokinetic data to reject the Panel’s recommendation to use a full weight– based dosing strategy for chemotherapeutic agents in patients with cancer who are obese, regardless of route of administration and/or infusion time. To date, there are no published pharmacogenetic articles meeting the inclusion and exclusion criteria for this guideline that could have been included in the discussion. Nevertheless, there may be a future role for applying pharmacokinetic and pharmacogenetic principles in cancer chemotherapy dosing to achieve a more personalized approach to treatment for the obese,146 although large prospective studies are certainly required to support this practice. who are accustomed to limiting chemotherapy doses for obese patients should be informed of the existing evidence. IV and oral doses may be prepackaged for patients of normal weight, but appropriate dosing should be delivered regardless of doses contained within a given vial. Arbitrary capping based on drug procurement costs is unacceptable (eg, one vial v 1.5 vials). The use of full weight– based dosing may have cost implications for payers, particularly if full weight– based doses of chemotherapy lead to more frequent use of WBC growth factors as prophylaxis to reduce the incidence of febrile neutropenia. If a suboptimal dose is administered initially, it should be increased to a full weight-based dose as tolerated. Patients need to be made aware of appropriate doses and be encouraged to monitor dose changes. HEALTH DISPARITIES Some racial and ethnic minorities and patients of lower socioeconomic status (SES) are at risk of suboptimal cancer care. Members of some racial and ethnic minority groups and patients with fewer financial resources tend to have a higher burden of comorbid illness, are more likely to be uninsured or underinsured, and face greater challenges in accessing high-quality health care.147-149 Awareness of disparities in quality of chemotherapy dose selection should be considered in context. Black/African American patients and patients of lower SES are more likely to receive reduced doses of adjuvant chemotherapy in the treatment of breast cancer.19,150 The higher rates of obesity among blacks/African Americans, Hispanics/Latinos, and people of lower SES151-153 only increase the likelihood of chemotherapy dose limits among these patients, who already experience higher case-fatality rates.154 Up to 40% of obese patients with breast cancer receive substantially reduced chemotherapy doses (⬎ 10% to 15% dose reduction), compared with doses that would be administered if actual body weight were used in dose calculations.13,51 Given the systematic differences in chemotherapy dose selection, it may be that black/African American women and women of lower SES will reap the greatest benefits from a change in the common practice of dose limitations in obese patients to full weight– based dosing. It is reassuring that there is no evidence that toxicity is more likely to occur when full weight– based doses are used.13,28,113,155,156 PATIENT AND CLINICIAN COMMUNICATION LIMITATIONS OF THE RESEARCH AND FUTURE DIRECTIONS Chemotherapy dose selection generally lies within the purview of the treating physician. If obese patients or caregivers inquire about dosing, however, a discussion of the evidence contained within this guideline is appropriate. Physicians may have to explain to obese patients and caregivers that higher doses are needed to be effective. In fact, suboptimal treatment could result if dosing is not full weight based. It is important to reassure patients that toxicity from the appropriate dose of chemotherapy is not expected to be greater. Adverse effects will be monitored closely. Patients should be warned that costs, even insurance copays, may be higher. Communication with other health care providers is also warranted, particularly if the use of full weight– based dosing has not been the practice in a given setting. Pharmacists and nursing professionals 8 © 2012 by American Society of Clinical Oncology The most obvious limitation of the evidence provided in support of these guidelines is the limited number of prospective RCTs directly addressing the issue of weight-based dosing. A prospective systematic review of obese patients enrolled onto a (specific) Cooperative Group trial of this issue would be helpful. Nonetheless, in addition to RCTs supporting the small but significant incremental benefit of dose-intensified therapy compared with standard dose-intensity, several trials have demonstrated a substantial reduction in treatment efficacy, with reductions in relative dose-intensity below standard doses and schedules. Although still representing the gold standard for demonstrating clinical efficacy, RCTs also have several well-recognized limitations. Relevant RCTs are only available for the ASCO Guideline on Weight-Based Dosing most common malignancies (eg, breast, lung, and gynecologic cancers). Studying the impact of relatively small reductions in doseintensity would require a large sample size to have sufficient power to assess the impact on long-term outcomes such as OS. RCTs often use strict and limiting eligibility criteria, excluding patients with comorbidities commonly encountered in those with cancer, which may reduce the effectiveness or increase toxicity but which often disqualify the patients from the trial. Therefore, RCTs may not adequately address effectiveness in the broader, unselected cancer population with major medical comorbidities and treatment safety issues that may not emerge until years later. Given the data that do exist, many consider deliberate random assignment of patients with responsive and potentially curable malignancies to lower and potentially less effective dose-intensity to be unethical. However, a rigorous systematic review of data from a series of patients enrolled onto Cooperative Group trials— examining data on all patients (with and without comorbid conditions) who are defined as obese— could shed light on the issue of outcomes for obese patients with cancer. Therefore, for both economic and ethical reasons, it is unlikely that additional data from RCTs directly addressing this issue will become available. Fortunately, there are abundant and compelling supportive data from both prospective cohort studies and well-done retrospective analyses of RCTs, which have almost universally supported the clinical importance of maintaining relative dose-intensity in patients with cancer with responsive and potentially curable malignancies. Consistent pharmacokinetic and pharmacodynamic studies as well as data from preclinical models including human tumor xenografts and animal studies all provide a firm underlying basis for the recommendations provided in this guideline. Nevertheless, it is essential that the same rigorous attention to accepted measures of highquality RCTs (ie, study design, conduct, analysis, and reporting) be applied in non-RCT studies as well. It is also essential that the study hypothesis, study population, controls, measurements, analytic methods, and any subgroup analyses be defined a priori. Well-designed REFERENCES 1. Freireich EJ, Gehan EA, Rall DP, et al: Quantitative comparison of toxicity of anticancer agents in mouse, rat, hamster, dog, monkey, and man. Cancer Chemother Rep 50:219-244, 1966 2. Frei E 3rd, Canellos GP: Dose: A critical factor in cancer chemotherapy. Am J Med 69:585594, 1980 3. Lyman GH: Chemotherapy dose intensity and quality cancer care. Oncology (Williston Park) 20:16-25, 2006 4. Bonneterre J, Roche H, Kerbrat P, et al: Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol 23:2686-2693, 2005 5. Budman DR, Berry DA, Cirrincione CT, et al: Dose and dose intensity as determinants of outcome in the adjuvant treatment of breast cancer: The Cancer and Leukemia Group B. J Natl Cancer Inst 90:1205-1211, 1998 6. Lepage E, Gisselbrecht C, Haioun C, et al: Prognostic significance of received relative dose intensity in non-Hodgkin’s lymphoma patients: Application prospective studies with planned analysis of body composition and adverse events would be valuable. There is a real need for data on both toxicity and efficacy in special populations such as the obese. As new drugs are being developed, it is important for industry to at least provide pharmacokinetic and pharmacodynamic data in real-world subgroups that may have been excluded from the clinical trials. The Panel acknowledges that there are limitations to study results based on data not specifically designed for prospective randomized comparisons. It is clear that clinician dosing decisions for obese patients and missing and/or inaccurately recorded clinical data affect prognosis and response to treatment. Given the numerous challenges to conducting well-designed RCTs on appropriate dosing for obese patients, other study designs will need to play a prominent role in future research. However, optimal care must be the ultimate goal of research on appropriate chemotherapy dosing for obese adult patients with cancer. ADDITIONAL RESOURCES An Executive Summary of this guideline has been published in JCO. Data Supplements, including evidence tables, and clinical tools and resources can be found at www.asco.org/guidelines/wbd. Patient information is available at www.cancer.net. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Administrative support: Pamela B. Mangu Manuscript writing: All authors Final approval of manuscript: All authors to LNH-87 protocol—The GELA (Groupe d’Etude des Lymphomes de l’Adulte). Ann Oncol 4:651-656, 1993 7. Lyman GH: Chemotherapy dosing in obese patients with cancer: The need for evidence-based clinical practice guidelines. J Oncol Pract 7:17-18, 2011 8. Fung-Kee-Fung M, Oliver T, Elit L, et al: Optimal chemotherapy treatment for women with recurrent ovarian cancer. Curr Oncol 14:195-208, 2007 9. Hunter RJ, Navo MA, Thaker PH, et al: Dosing chemotherapy in obese patients: Actual versus assigned body surface area (BSA). Cancer Treat Rev 35:69-78, 2009 10. Lyman GH, Dale DC, Crawford J: Incidence and predictors of low dose-intensity in adjuvant breast cancer chemotherapy: A nationwide study of community practices. J Clin Oncol 21:4524-4531, 2003 11. Greenman CG, Jagielski CH, Griggs JJ: Breast cancer adjuvant chemotherapy dosing in obese patients: Dissemination of information from clinical trials to clinical practice. Cancer 112:21592165, 2008 12. Griggs JJ, Sabel MS: Obesity and cancer treatment: Weighing the evidence. J Clin Oncol 26:4060-4062, 2008 13. Griggs JJ, Sorbero ME, Lyman GH: Undertreatment of obese women receiving breast cancer chemotherapy. Arch Intern Med 165:1267-1273, 2005 14. Lyman GH: Impact of chemotherapy dose intensity on cancer patient outcomes. J Natl Compr Canc Netw 7:99-108, 2009 15. Lyman GH, Dale DC, Friedberg J, et al: Incidence and predictors of low chemotherapy dose-intensity in aggressive non-Hodgkin’s lymphoma: A nationwide study. J Clin Oncol 22:4302-4311, 2004 16. Field KM, Kosmider S, Jefford M, et al: Chemotherapy dosing strategies in the obese, elderly, and thin patient: Results of a nationwide survey. J Oncol Pract 4:108-113, 2008 17. Shayne M, Culakova E, Poniewierski MS, et al: Dose intensity and hematologic toxicity in older cancer patients receiving systemic chemotherapy. Cancer 110:1611-1620, 2007 18. Griggs JJ, Culakova E, Sorbero ME, et al: Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens. J Clin Oncol 25:2522-2527, 2007 19. Griggs JJ, Culakova E, Sorbero ME, et al: Effect of patient socioeconomic status and body mass index on the quality of breast cancer adjuvant chemotherapy. J Clin Oncol 25:277-284, 2007 © 2012 by American Society of Clinical Oncology 9 Griggs et al 20. Griggs JJ, Sorbero ME: Cost effectiveness, chemotherapy, and the clinician. Breast Cancer Res Treat 114:597-598, 2009 21. Lyman GH: A novel approach to maintain planned dose chemotherapy on time: A decisionmaking tool to improve patient care. Eur J Cancer 36:S15-S21, 2000 (suppl 1) 22. Grigg A, Harun MH, Szer J: Variability in determination of body weight used for dosing busulphan and cyclophosphamide in adult patients: Results of an international survey. Leuk Lymphoma 25:487-491, 1997 23. Dale DC, McCarter GC, Crawford J, et al: Myelotoxicity and dose intensity of chemotherapy: Reporting practices from randomized clinical trials. J Natl Compr Canc Netw 1:440-454, 2003 24. Centers for Disease Control and Prevention: Overweight and obesity. http://www.cdc.gov/obesity/ index.html 25. Wang YC, McPherson K, Marsh T, et al: Health and economic burden of the projected obesity trends in the USA and the UK. Lancet 378:815825, 2011 26. Organisation for Economic Co-operation and Development: Obesity and the economics of prevention: Fit not fat. http://www.oecd.org/document/31/ 0,3343,en_2649_33929_45999775_1_1_1_1,00.html 27. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625-1638, 2003 28. Rosner GL, Hargis JB, Hollis DR, et al: Relationship between toxicity and obesity in women receiving adjuvant chemotherapy for breast cancer: Results from Cancer and Leukemia Group B study 8541. J Clin Oncol 14:3000-3008, 1996 29. Georgiadis MS, Steinberg SM, Hankins LA, et al: Obesity and therapy-related toxicity in patients treated for small-cell lung cancer. J Natl Cancer Inst 87:361-366, 1995 30. Poikonen P, Blomqvist C, Joensuu H: Effect of obesity on the leukocyte nadir in women treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil dosed according to body surface area. Acta Oncol 40:67-71, 2001 31. Superfin D, Iannucci AA, Davies AM: Oncologic drugs in patients with organ dysfunction: A summary. Oncologist 12:1070-1083, 2007 32. Smorenburg CH, Sparreboom A, Bontenbal M, et al: Randomized cross-over evaluation of bodysurface area-based dosing versus flat-fixed dosing of paclitaxel. J Clin Oncol 21:197-202, 2003 33. Fuchs CS, Moore MR, Harker G, et al: Phase III comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol 21:807-814, 2003 34. Yamamoto N, Tamura T, Murakami H, et al: Randomized pharmacokinetic and pharmacodynamic study of docetaxel: Dosing based on bodysurface area compared with individualized dosing based on cytochrome P450 activity estimated using a urinary metabolite of exogenous cortisol. J Clin Oncol 23:1061-1069, 2005 35. Soo RA, Wang LZ, Tham LS, et al: A multicenter randomized phase II study of carboplatin in combination with gemcitabine at standard rate or fixed dose rate infusion in patients with advanced stage non-small-cell lung cancer. Ann Oncol 17: 1128-1133, 2006 36. Budman DR: Dose and schedule as determinants of outcomes in chemotherapy for breast cancer. Semin Oncol 31:3-9, 2004 37. Sculier JP, Paesmans M, Thiriaux J, et al: A comparison of methods of calculation for estimating 10 © 2012 by American Society of Clinical Oncology carboplatin AUC with a retrospective pharmacokineticpharmacodynamic analysis in patients with advanced non-small cell lung cancer: European Lung Cancer Working Party. Eur J Cancer 35:1314-1319, 1999 38. de Jongh FE, Verweij J, Loos WJ, et al: Body-surface area– based dosing does not increase accuracy of predicting cisplatin exposure. J Clin Oncol 19:3733-3739, 2001 39. Sawyer M, Ratain MJ: Body surface area as a determinant of pharmacokinetics and drug dosing. Invest New Drugs 19:171-177, 2001 40. Baker SD, Verweij J, Rowinsky EK, et al: Role of body surface area in dosing of investigational anticancer agents in adults, 1991-2001. J Natl Cancer Inst 94:1883-1888, 2002 41. Felici A, Verweij J, Sparreboom A: Dosing strategies for anticancer drugs: The good, the bad and body-surface area. Eur J Cancer 38:1677-1684, 2002 42. Gurney H: How to calculate the dose of chemotherapy. Br J Cancer 86:1297-1302, 2002 43. Smorenburg CH, ten Tije AJ, Verweij J, et al: Altered clearance of unbound paclitaxel in elderly patients with metastatic breast cancer. Eur J Cancer 39:196-202, 2003 44. Sparreboom A, Verweij J: Paclitaxel pharmacokinetics, threshold models, and dosing strategies. J Clin Oncol 21:2803-2804, 2003; author reply 28052806 45. de Jong FA, Mathijssen RH, Xie R, et al: Flat-fixed dosing of irinotecan: Influence on pharmacokinetic and pharmacodynamic variability. Clin Cancer Res 10:4068-4071, 2004 46. Miller AA, Rosner GL, Egorin MJ, et al: Prospective evaluation of body surface area as a determinant of paclitaxel pharmacokinetics and pharmacodynamics in women with solid tumors: Cancer and Leukemia Group B study 9763. Clin Cancer Res 10:8325-8331, 2004 47. Rudek MA, Sparreboom A, Garrett-Mayer ES, et al: Factors affecting pharmacokinetic variability following doxorubicin and docetaxel-based therapy. Eur J Cancer 40:1170-1178, 2004 48. Sparreboom A: BSA-based dosing and alternative approaches. Clin Adv Hematol Oncol 3:448450, 2005 49. Mross K, Holländer N, Frost A, et al: PAC fixed dose: Pharmacokinetics of a 1-hour paclitaxel infusion and comparison to BSA-normalized drug dosing. Onkologie 29:444-450, 2006 50. Mathijssen RH, de Jong FA, Loos WJ, et al: Flat-fixed dosing versus body surface area based dosing of anticancer drugs in adults: Does it make a difference? Oncologist 12:913-923, 2007 51. Colleoni M, Li S, Gelber RD, et al: Relation between chemotherapy dose, oestrogen receptor expression, and body-mass index. Lancet 366:11081110, 2005 52. Hryniuk W, Frei E 3rd, Wright FA: A single scale for comparing dose-intensity of all chemotherapy regimens in breast cancer: Summation doseintensity. J Clin Oncol 16:3137-3147, 1998 53. Hryniuk W, Ragaz J, Peters W: Dose density by any other name. J Clin Oncol 22:750-751, 2004; author reply 751-753 54. Hryniuk W, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2:1281-1288, 1984 55. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4:1162-1170, 1986 56. Hryniuk WM, Figueredo A, Goodyear M: Applications of dose intensity to problems in chem- otherapy of breast and colorectal cancer. Semin Oncol 14:3-11, 1987 57. Hryniuk WM: Average relative dose intensity and the impact on design of clinical trials. Semin Oncol 14:65-74, 1987 58. Hryniuk WM: Integrating the concept of dose intensity into a strategy for systemic therapy of malignant disease. Prog Clin Biol Res 354B:93-101, 1990 59. Hryniuk WM, Goodyear M: The calculation of received dose intensity. J Clin Oncol 8:1935-1937, 1990 60. Venook AP, Egorin MJ, Rosner GL, et al: Phase I and pharmacokinetic trial of paclitaxel in patients with hepatic dysfunction: Cancer and Leukemia Group B 9264. J Clin Oncol 16:1811-1819, 1998 61. Lichtman SM, Skirvin JA, Vemulapalli S: Pharmacology of antineoplastic agents in older cancer patients. Crit Rev Oncol Hematol 46:101-114, 2003 62. Lichtman SM, Hollis D, Miller AA, et al: Prospective evaluation of the relationship of patient age and paclitaxel clinical pharmacology: Cancer and Leukemia Group B (CALGB 9762). J Clin Oncol 24:1846-1851, 2006 63. Lichtman SM, Wildiers H, Launay-Vacher V, et al: International Society of Geriatric Oncology (SIOG) recommendations for the adjustment of dosing in elderly cancer patients with renal insufficiency. Eur J Cancer 43:14-34, 2007 64. Lichtman SM, Wildiers H, Chatelut E, et al: International Society of Geriatric Oncology Chemotherapy Taskforce: Evaluation of chemotherapy in older patients—An analysis of the medical literature. J Clin Oncol 25:1832-1843, 2007 65. Lichtman SM: Pharmacokinetics and pharmacodynamics in the elderly. Clin Adv Hematol Oncol 5:181-182, 2007 66. Gurney H: Dose calculation of anticancer drugs: A review of the current practice and introduction of an alternative. J Clin Oncol 14:2590-2611, 1996 67. Gurney H, Shaw R: Obesity in dose calculation: A mouse or an elephant? J Clin Oncol 25:47034704, 2007 68. Green B, Duffull SB: What is the best size descriptor to use for pharmacokinetic studies in the obese? Br J Clin Pharmacol 58:119-133, 2004 69. Muss HB, Woolf S, Berry D, et al: Adjuvant chemotherapy in older and younger women with lymph node-positive breast cancer. JAMA 293: 1073-1081, 2005 70. ten Tije AJ, Verweij J, Carducci MA, et al: Prospective evaluation of the pharmacokinetics and toxicity profile of docetaxel in the elderly. J Clin Oncol 23:1070-1077, 2005 71. Wasil T, Lichtman SM: Clinical pharmacology issues relevant to the dosing and toxicity of chemotherapy drugs in the elderly. Oncologist 10:602612, 2005 72. Loos WJ, de Jongh FE, Sparreboom A, et al: Evaluation of an alternate dosing strategy for cisplatin in patients with extreme body surface area values. J Clin Oncol 24:1499-1506, 2006 73. Hempel G, Boos J: Flat-fixed dosing versus body surface area based dosing of anticancer drugs: There is a difference. Oncologist 12:924-926, 2007 74. Launay-Vacher V, Chatelut E, Lichtman SM, et al: Renal insufficiency in elderly cancer patients: International Society of Geriatric Oncology clinical practice recommendations. Ann Oncol 18:13141321, 2007 ASCO Guideline on Weight-Based Dosing 75. Muss HB, Berry DA, Cirrincione C, et al: Toxicity of older and younger patients treated with adjuvant chemotherapy for node-positive breast cancer: The Cancer and Leukemia Group B Experience. J Clin Oncol 25:3699-3704, 2007 76. Sparreboom A: Unexplored pharmacokinetic opportunities with microdosing in oncology. Clin Cancer Res 13:4033-4034, 2007 77. Wildiers H: Mastering chemotherapy dose reduction in elderly cancer patients. Eur J Cancer 43:2235-2241, 2007 78. Barbolosi D, Iliadis A: Optimizing drug regimens in cancer chemotherapy: A simulation study using a PK-PD model. Comput Biol Med 31:157-172, 2001 79. Bonadonna G, Valagussa P: Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 304:10-15, 1981 80. Bonadonna G, Valagussa P, Moliterni A, et al: Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: The results of 20 years of follow-up. N Engl J Med 332:901-906, 1995 81. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: Prospective evaluation of a simple formula based on renal function. J Clin Oncol 7:1748-1756, 1989 82. Chang J: Chemotherapy dose reduction and delay in clinical practice: Evaluating the risk to patient outcome in adjuvant chemotherapy for breast cancer. Eur J Cancer 36:S11-S4, 2000 (suppl 1) 83. Cornelison TL, Reed E: Dose intensity analysis of high-dose carboplatin in refractory ovarian carcinoma relative to age. Cancer 71:650-655, 1993 84. Foote M: The importance of planned dose of chemotherapy on time: Do we need to change our clinical practice? Oncologist 3:365-368, 1998 85. Gianni AM, Piccart MJ: Optimizing chemotherapy dose density and dose intensity: New strategies to improve outcomes in adjuvant therapy for breast cancer. Eur J Cancer 36:S1-S3, 2000 (suppl 1) 86. Holmberg L, Tamini R: Reducing cancer drug doses in obese patients: Dogma disputed. Lancet 366:1056-1057, 2005 87. Kwak LW, Halpern J, Olshen RA, et al: Prognostic significance of actual dose intensity in diffuse large-cell lymphoma: Results of a treestructured survival analysis. J Clin Oncol 8:963-977, 1990 88. Lenhart C: Relative dose intensity: Improving cancer treatment and outcomes. Oncol Nurs Forum 32:757-764, 2005 89. Levin L, Hryniuk W: The application of dose intensity to problems in chemotherapy of ovarian and endometrial cancer. Semin Oncol 14:12-19, 1987 90. Levin L, Hryniuk WM: Dose intensity analysis of chemotherapy regimens in ovarian carcinoma. J Clin Oncol 5:756-767, 1987 91. Longo DL, Duffey PL, DeVita VT Jr, et al: The calculation of actual or received dose intensity: A comparison of published methods. J Clin Oncol 9:2042-2051, 1991 92. Mosteller RD: Simplified calculation of bodysurface area. N Engl J Med 317:1098, 1987 93. Meyer RM, Hryniuk WM, Goodyear MD: The role of dose intensity in determining outcome in intermediate-grade non-Hodgkin’s lymphoma. J Clin Oncol 9:339-347, 1991 94. Muggia FM: Relevance of chemotherapy dose and schedule to outcomes in ovarian cancer. Semin Oncol 31:19-24, 2004 95. Repetto L, Pace M, Mammoliti S, et al: The impact of received dose intensity on the outcome of advanced ovarian cancer. Eur J Cancer 29A:181184, 1993 96. Dobbs NA, Twelves CJ: What is the effect of adjusting epirubicin doses for body surface area? Br J Cancer 78:662-666, 1998 97. Sparreboom A, Wolff AC, Mathijssen RH, et al: Evaluation of alternate size descriptors for dose calculation of anticancer drugs in the obese. J Clin Oncol 25:4707-4713, 2007 98. Centers for Disease Control and Prevention: Body mass index. http://www.cdc.gov/healthyweight/ assessing/bmi/index.html 99. Schwartz J, Toste B, Dizon DS: Chemotherapy toxicity in gynecologic cancer patients with a body surface area (BSA)⬎2 m2. Gynecol Oncol 114:53-56, 2009 100. Meyerhardt JA, Niedzwiecki D, Hollis D, et al: Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: Findings from Cancer and Leukemia Group B 89803. J Clin Oncol 26:4109-4115, 2008 101. Meyerhardt JA, Catalano PJ, Haller DG, et al: Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 98:484-495, 2003 102. Meyerhardt JA, Tepper JE, Niedzwiecki D, et al: Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: Findings from Intergroup Trial 0114. J Clin Oncol 22:648-657, 2004 103. Barrett SV, Paul J, Hay A, et al: Does body mass index affect progression-free or overall survival in patients with ovarian cancer? Results from SCOTROC I trial. Ann Oncol 19:898-902, 2008 104. Pavlovsky C, Egorin MJ, Shah DD, et al: Imatinib mesylate pharmacokinetics before and after sleeve gastrectomy in a morbidly obese patient with chronic myeloid leukemia. Pharmacotherapy 29:1152-1156, 2009 105. Ritzmo C, Soderhall S, Karlen J, et al: Pharmacokinetics of doxorubicin and etoposide in a morbidly obese pediatric patient. Pediatr Hematol Oncol 24:437-445, 2007 106. Friedenreich C, Cust A, Lahmann PH, et al: Anthropometric factors and risk of endometrial cancer: The European prospective investigation into cancer and nutrition. Cancer Causes Control 18:399413, 2007 107. Modesitt SC, Tian C, Kryscio R, et al: Impact of body mass index on treatment outcomes in endometrial cancer patients receiving doxorubicin and cisplatin: A Gynecologic Oncology Group study. Gynecol Oncol 105:59-65, 2007 108. Shehan JM, Ahmed I: Angiosarcoma arising in a lymphedematous abdominal pannus with histologic features reminiscent of Kaposi’s sarcoma: Report of a case and review of the literature. Int J Dermatol 45:499-503, 2006 109. Baker SD, van Schaik RH, Rivory LP, et al: Factors affecting cytochrome P-450 3A activity in cancer patients. Clin Cancer Res 10:8341-8350, 2004 110. Azam M, Saboorian H, Bieligk S, et al: Cutaneous angiosarcoma complicating morbid obesity. Arch Pathol Lab Med 125:531-533, 2001 111. Ritchie DS, Wirth A, Grigg AP: Successful transplant outcome in a morbidly obese patient with acute myeloblastic leukemia. Leuk Lymphoma 42: 1111-1114, 2001 112. Ahmad NA, Memon A, Hussainy A: Abdominoperineal excision of male lower urinary tract for synchronous adenocarcinoma of urethra and urinary bladder. Urology 65:591, 2005 113. Smith TJ, Desch CE: Neutropenia-wise and pound-foolish: Safe and effective chemotherapy in massively obese patients. South Med J 84:883-885, 1991 114. Colangelo PM, Welch DW, Rich DS, et al: Two methods for estimating body surface area in adult amputees. Am J Hosp Pharm 41:2650-2655, 1984 115. Madarnas Y, Sawka CA, Franssen E, et al: Are medical oncologists biased in their treatment of the large woman with breast cancer? Breast Cancer Res Treat 66:123-133, 2001 116. Wright JD, Tian C, Mutch DG, et al: Carboplatin dosing in obese women with ovarian cancer: A Gynecologic Oncology Group study. Gynecol Oncol 109:353-358, 2008 117. Abdah-Bortnyak R, Tsalic M, Haim N: Actual body weight for determining doses of chemotherapy in obese cancer patients: Evaluation of treatment tolerability. Med Oncol 20:363-368, 2003 118. Lopes-Serrao MD, Ussery SM, Hall RG 2nd, et al: Evaluation of chemotherapy-induced severe myelosuppression incidence in obese patients with capped dosing. J Oncol Pract 7:13-17, 2011 119. Carboplatin dose calculator. https://hccapps .musc.edu/hemonc/carboplatin_dose_calculator.htm 120. Okamoto H, Nagatomo A, Kunitoh H, et al: Prediction of carboplatin clearance calculated by patient characteristics or 24-hour creatinine clearance: A comparison of the performance of three formulae. Cancer Chemother Pharmacol 42:307312, 1998 121. US Department of Health and Human Services: Follow-up for information letter regarding AUC-based dosing of carboplatin. ctep.cancer.gov/ content/docs/Carboplatin_Information_Letter.pdf 122. Schmitt A, Gladieff L, Lansiaux A, et al: A universal formula based on cystatin C to perform individual dosing of carboplatin in normal weight, underweight, and obese patients. Clin Cancer Res 15:3633-3639, 2009 123. Ekhart C, Rodenhuis S, Schellens JH, et al: Carboplatin dosing in overweight and obese patients with normal renal function, does weight matter? Cancer Chemother Pharmacol 64:115122, 2009 124. Einhorn LH: Curing metastatic testicular cancer. Proc Natl Acad Sci U S A 99:4592-4595, 2002 125. Coiffier B, Lepage E, Briere J, et al: CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235-242, 2002 126. Pfreundschuh M, Trümper L, Osterborg A, et al: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomized controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 7:379-391, 2006 127. Mathijssen RH, Verweij J, de Jonge MJ, et al: Impact of body-size measures on irinotecan clearance: Alternative dosing recommendations. J Clin Oncol 20:81-87, 2002 128. Borne E, Desmedt E, Duhamel A, et al: Oral metronomic cyclophosphamide in elderly with metastatic melanoma. Invest New Drugs 28:684-689, 2010 129. Fontana A, Galli L, Fioravanti A, et al: Clinical and pharmacodynamic evaluation of metronomic cyclophosphamide, celecoxib, and dexamethasone © 2012 by American Society of Clinical Oncology 11 Griggs et al in advanced hormone-refractory prostate cancer. Clin Cancer Res 15:4954-4962, 2009 130. Fontana A, Bocci G, Galli L, et al: Metronomic cyclophosphamide in elderly patients with advanced, castration-resistant prostate cancer. J Am Geriatr Soc 58:986-988, 2010 131. Ladoire S, Eymard JC, Zanetta S, et al: Metronomic oral cyclophosphamide prednisolone chemotherapy is an effective treatment for metastatic hormone-refractory prostate cancer after docetaxel failure. Anticancer Res 30:4317-4323, 2010 132. Penel N, Clisant S, Dansin E, et al: Megestrol acetate versus metronomic cyclophosphamide in patients having exhausted all effective therapies under standard care. Br J Cancer 102:1207-1212, 2010 133. Rabinowits G, Bhupalam L, Miller DM, et al: Fixed-dose every-other-week capecitabine and oxaliplatin for refractory squamous cell carcinoma of the head and neck. Am J Med Sci 339:148-151, 2010 134. Prado CM, Baracos VE, McCargar LJ, et al: Body composition as an independent determinant of 5-fluorouracil-based chemotherapy toxicity. Clin Cancer Res 13:3264-3268, 2007 135. Sparreboom A, Loos WJ, De Jonge MJ, et al: Clinical trial design: Incorporation of pharmacokinetic, pharmacodynamic and pharmacogenetic principles, in Baguley BC, Kerr DJ (eds): Anticancer Drug Development. Philadelphia, PA, Academic Press, 2002, pp 329-351 136. Emery MG, Fisher JM, Chien JY, et al: CYP2E1 activity before and after weight loss in morbidly obese subjects with nonalcoholic fatty liver disease. Hepatology 38:428-435, 2003 137. Hanley MJ, Abernethy DR, Greenblatt DJ: Effect of obesity on the pharmacokinetics of drugs in humans. Clin Pharmacokinet 49:71-87, 2010 138. Han PY, Duffull SB, Kirkpatrick CM, et al: Dosing in obesity: A simple solution to a big problem. Clin Pharmacol Ther 82:505-508, 2007 139. Mathijssen RH, Sparreboom A: Influence of lean body weight on anticancer drug clearance. Clin Pharmacol Ther 85:23, 2009; author reply 24 140. Blouin RA, Kolpek JH, Mann HJ: Influence of obesity on drug disposition. Clin Pharm 6:706-714, 1987 141. Gibbs JP, Gooley T, Corneau B, et al: The impact of obesity and disease on busulfan oral clearance in adults. Blood 93:4436-4440, 1999 142. Nguyen L, Leger F, Lennon S, et al: Intravenous busulfan in adults prior to hematopoietic stem cell transplantation: A population pharmacokinetic study. Cancer Chemother Pharmacol 57:191-198, 2006 143. Bénézet S, Guimbaud R, Chatelut E, et al: How to predict carboplatin clearance from standard morphological and biological characteristics in obese patients. Ann Oncol 8:607-609, 1997 144. Schmitt A, Gladieff L, Laffont CM, et al: Factors for hematopoietic toxicity of carboplatin: Refining the targeting of carboplatin systemic exposure. J Clin Oncol 28:4568-4574, 2010 145. Rodvold KA, Rushing DA, Tewksbury DA: Doxorubicin clearance in the obese. J Clin Oncol 6:1321-1327, 1988 146. De Jonge ME, Mathot RA, Van Dam SM, et al: Extremely high exposures in an obese patient receiving high-dose cyclophosphamide, thiotepa and carboplatin. Cancer Chemother Pharmacol 50: 251-255, 2002 147. Smedley BD, Stith AY, Nelson AR (eds): Unequal Treatment: Confronting Racial and Ethnic Disparities in Health Care. Washington, DC, National Academies Press, 2003 148. Mead H, Cartwright-Smith L, Jones K, et al: Racial and Ethnic Disparities in U.S. Health Care: A Chartbook. New York, NY, The Commonwealth Fund, 2008 149. Centers for Disease Control and Prevention: National Center for Health Statistics: Health, United States, 2010. http://www.cdc.gov/nchs/hus.htm 150. Griggs JJ, Sorbero ME, Stark AT, et al: Racial disparity in the dose and dose intensity of breast cancer adjuvant chemotherapy. Breast Cancer Res Treat 81:21-31, 2003 151. Wang Y, Beydoun MA: The obesity epidemic in the United States: Gender, age, socioeconomic, racial/ethnic, and geographic characteristics—A systematic review and meta-regression analysis. Epidemiol Rev 29:6-28, 2007 152. Cossrow N, Falkner B: Race/ethnic issues in obesity and obesity-related comorbidities. J Clin Endocrinol Metab 89:2590-2594, 2004 153. Liao Y, Tucker P, Okoro CA, et al: REACH 2010 surveillance for health status in minority communities: United States, 2001-2002. MMWR Surveill Summ 53:1-36, 2004 154. Ward E, Jemal A, Cokkinides V, et al: Cancer disparities by race/ethnicity and socioeconomic status. CA Cancer J Clin 54:78-93, 2004 155. Jenkins P, Elyan S, Freeman S: Obesity is not associated with increased myelosuppression in patients receiving chemotherapy for breast cancer. Eur J Cancer 43:544-548, 2007 156. Smith K, Wray L, Klein-Cabral M, et al: Ethnic disparities in adjuvant chemotherapy for breast cancer are not caused by excess toxicity in black patients. Clin Breast Cancer 6:260-266, 2005; discussion 267-269 ■ ■ ■ Acknowledgment The Panel wishes to express its gratitude to Howard Gurney, MBBS, Robert J. Mayer, MD, Alok A. Khorana, MD, Sharon H. Giordano, MD, and members of the American Society of Clinical Oncology Clinical Practice Guideline Committee for their thoughtful reviews of earlier drafts. Appendix Table A1. Expert Panel Members Member Affiliation Jennifer J. Griggs, MD, MPH, Co-Chair Gary H. Lyman, MD, MPH, FRCP, Co-Chair Holly Anderson Edward P. Balaban, DO James J. Dignam, PhD William M. Hryniuk, MD Vicki A. Morrison, MD T. May Pini, MD, MPH Carolyn D. Runowicz, MD Gary L. Rosner, ScD Michelle Shayne, MD Alex Sparreboom, PhD Lara E. Sucheston, PhD Department of Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI Duke University and Duke Cancer Institute, Durham, NC Patient Representative, Breast Cancer Coalition of Rochester, Rochester, NY University of Pittsburgh Cancer Centers Network, Pittsburgh, PA Department of Health Studies, University of Chicago, Chicago, IL CarePath, Toronto, Ontario, Canada University of Minnesota Veterans Affairs Medical Center, Minneapolis, MN Medical Oncology, Houston, TX Florida International University, Miami, FL Division of Oncology Biostatistics and Bioinformatics, Johns Hopkins University, Baltimore, MD University of Rochester Medical Center, Rochester, NY St Jude Children’s Research Hospital, Memphis, TN Roswell Park Cancer Institute, Cancer Prevention and Control, Buffalo, NY 12 © 2012 by American Society of Clinical Oncology